There are six known herpes-type viruses which affect human beings: herpes zoster (chicken pox), herpes simplex virus I & II (cold sores and genital herpes), cytomegalovirus (cytomegalic inclusion disease), Epstein-Barr virus (mononucleosis), and the recently isolated Herpes VI virus. The herpes viruses are medium-sized viruses containing double-stranded DNA, with a nucleocapsid about 100 nm in diameter surrounded by a lipid-containing envelope. The virion is 150-200 nm in diameter and permits latent infections which last for the life span of the host even when antibodies are present.
The present invention is specifically directed to novel compounds which have been found useful for treating cytomegalovirus. Human cytomegalovirus is a ubiquitous agent in human populations. Infections are generally asymptomatic, but there can be serious medical manifestations of the disease in immunocompromised individuals (e.g., transplant recipients and AIDS patients) and in congenitally infected newborns. Present drug therapies for treating CMV are not always effective, insofar as the virus may be resistant to the commonly used nucleoside-type pharmaceuticals such as ganciclovir and foscarnet. Additionally, the former drug, when combined with the AIDS drug azidothymidine ("AZT"), a dideoxynucleoside, can give rise to synergistic toxicity, and thus is severely limited in its usefulness for treating CMV in AIDS patients.
The antiviral agents of the invention are novel nonnucleoside compounds which will be described in detail hereinbelow. Because these compounds are not nucleosides or nucleoside analogs, they operate by an entirely different mechanism of action than do the compounds of the prior art, and do not result in the disadvantages associated with those compounds.
Several references are of interest which relate to benzothiophene analogs as pharmaceutical agents. These include U.S. Pat. Nos. 4,045,565, 4,310,667 and 4,483,989 to Le Pecq et al., 4,851,417 to Archer, and U.S. Pat. No. 4,897,398 to Gros et al. All of the aforementioned patents relate to benzothiophene analogs in the form of 9-hydroxy ellipticine or derivatives thereof, as anti-cancer agents. U.S. Pat. No. 3,933,827 to Brossi et al. and 4,334,070 to Berger et al. describe similar compounds as cytostatic agents and antipsychotic drugs, respectively. These references do not, however, suggest or disclose the newly discovered compounds described herein, nor do they suggest that benzothiophene or ellipticene derivatives would be useful to treat herpes viruses in general, or CMV in particular.